European Achondroplasia Forum Practical Considerations for Following Adults with Achondroplasia.

Achondroplasia is a lifelong condition requiring lifelong management. There is consensus that infants and children with achondroplasia should be managed by a multidisciplinary team experienced in the condition. However, many people are lost to follow-up after the transition from paediatric to adult care, and there is no standardised approach for management in adults, despite the recent availability of international consensus guidelines. To address this, the European Achondroplasia Forum has developed a patient-held checklist to support adults with achondroplasia in managing their health. The checklist highlights key symptoms of spinal stenosis and obstructive sleep apnoea, both among the most frequent and potentially severe medical complications in adults with achondroplasia. The checklist acts as a framework to support individuals and their primary care provider in completing a routine review. General advice on issues such as blood pressure, pain, hearing, weight, adaptive aids, and psychosocial aspects are also included. The checklist provides key symptoms to be aware of, in addition to action points so that people can approach their primary care provider and be directed to the appropriate specialist, if needed. Additionally, the European Achondroplasia Forum offers some ideas on implementing the checklist during the transition from paediatric to adult care, thus ensuring the existing multidisciplinary team model in place during childhood can support in engaging individuals and empowering them to take responsibility for their own care as they move into adulthood.

European Achondroplasia Forum guiding principles for the detection and management of foramen magnum stenosis.

Foramen magnum stenosis is a serious, and potentially life-threatening complication of achondroplasia. The foramen magnum is smaller in infants with achondroplasia, compared with the general population, and both restricted growth in the first 2 years and premature closure of skull plate synchondroses can contribute to narrowing. Narrowing of the foramen magnum can lead to compression of the brainstem and spinal cord, and result in sleep apnoea and sudden death. There is a lack of clarity in the literature on the timing of regular monitoring for foramen magnum stenosis, which assessments should be carried out and when regular screening should be ceased. The European Achondroplasia Forum (EAF) is a group of clinicians and patient advocates, representative of the achondroplasia community. Members of the EAF Steering Committee were invited to submit suggestions for guiding principles for the detection and management of foramen magnum stenosis, which were collated and discussed at an open workshop. Each principle was scrutinised for content and wording, and anonymous voting held to pass the principle and vote on the level of agreement. A total of six guiding principles were developed which incorporate routine clinical monitoring of infants and young children, timing of routine MRI screening, referral of suspected foramen magnum stenosis to a neurosurgeon, the combination of assessments to inform the decision to decompress the foramen magnum, joint decision making to proceed with decompression, and management of older children in whom previously undetected foramen magnum stenosis is identified. All principles achieved the ≥ 75% majority needed to pass (range 89-100%), with high levels of agreement (range 7.6-8.9). By developing guiding principles for the detection and management of foramen magnum stenosis, the EAF aim to enable infants and young children to receive optimal monitoring for this potentially life-threatening complication.

Optimising care and follow-up of adults with achondroplasia.

BACKGROUND: Achondroplasia is a genetic condition that can cause complications across the lifespan. While complications in childhood are well documented, the natural history of achondroplasia in adults has, until recently, been relatively lacking, and little is known about the care they receive or how they access it. The European Achondroplasia Forum undertook two exploratory surveys, one for healthcare professionals (HCPs) and one for patient advocacy group (PAG) representatives, to gain an understanding of current practices of the transition process of individuals with achondroplasia from paediatric to adult services and how adults perceive their care. RESULTS: Most HCP respondents followed up more children than adults, and 8/15 responded that individuals did not transition to an adult multidisciplinary team (MDT) after paediatric care. Of 10 PAG respondents, none considered the experience of transition to adult services as good or very good and 50% considered it to be poor or very poor. A total of 64% (7/11) described the coordination of transition to adult services as "Not satisfactory" or "Poor". HCPs and PAG representatives largely agreed on the core specialists involved in adult care (orthopaedic surgeons, physiotherapists, rehabilitation specialists, rheumatologists, clinical geneticists). However, there was a discrepancy in the understanding of healthcare needs outside of this, with PAG representatives selecting neurosurgeons and genetic counsellors, while HCPs selected pulmonologists and obstetricians/gynaecologists. There was agreement between HCP and PAG respondents on the key barriers to effective care of adults with achondroplasia, with lack of an adult MDT, lack of interest from individuals in accessing care, and less experience in adult than paediatric MDTs ranking highly. CONCLUSIONS: This study indicates that the care and follow up of adults with achondroplasia is challenging. Individuals are often lost to, or decline, follow up as they leave paediatric care, and it is largely unknown how, where, and why adults with achondroplasia access care later in life. Lifelong, multidisciplinary specialist care led by an identified physician should be accessible to all individuals with achondroplasia. It is important to ensure barriers to optimal care are addressed to enable access to appropriate care for all individuals with achondroplasia.

Optimising the diagnosis and referral of achondroplasia in Europe: European Achondroplasia Forum best practice recommendations.

BACKGROUND: Achondroplasia is the most common form of skeletal dysplasia, with serious comorbidities and complications that may occur from early infancy to adulthood, requiring lifelong management from a multidisciplinary team expert in the condition The European Achondroplasia Forum guiding principles of management highlight the importance of accurate diagnosis and timely referral to a centre specialised in the management of achondroplasia to fully support individuals with achondroplasia and their families, and to appropriately plan management. The European Achondroplasia Forum undertook an exploratory audit of its Steering Committee to ascertain the current situation in Europe and to understand the potential barriers to timely diagnosis and referral. RESULTS: Diagnosis of achondroplasia was primarily confirmed prenatally (66.6%), at Day 0 (12.8%) or within one month after birth (12.8%). For suspected and confirmed cases of achondroplasia, a greater proportion were identified earlier in the prenatal period (87.1%) with fewer diagnoses at Day 0 (5.1%) or within the first month of life (2.6%). Referral to a specialist centre took place after birth (86.6%), predominantly within the first month, although there was a wide variety in the timepoint of referral between countries and in the time lapsed between suspicion or confirmed diagnosis of achondroplasia and referral to a specialist centre. CONCLUSIONS: The European Achondroplasia Forum guiding principles of management recommend diagnosis of achondroplasia as early as possible. If concerns are raised at routine ultrasound, second line investigation should be implemented so that the diagnosis can be reached as soon as possible for ongoing management. Clinical and radiological examination supported by molecular testing is the most effective way to confirm diagnosis of achondroplasia after birth. Referral to a centre specialised in achondroplasia care should be made as soon as possible on suspicion or confirmation of diagnosis. In countries or regions where there are no official skeletal dysplasia reference or specialist centres, priority should be given to their creation or recognition, together with incentives to improve the structure of the existing multidisciplinary team managing achondroplasia. The length of delay between diagnosis of achondroplasia and referral to a specialist centre warrants further research.

The first European consensus on principles of management for achondroplasia.

Achondroplasia is the most common type of skeletal dysplasia, caused by a recurrent pathogenic variant in the fibroblast growth factor receptor 3 (FGFR3). The management of achondroplasia is multifaceted, requiring the involvement of multiple specialties across the life course. There are significant unmet needs associated with achondroplasia and substantial differences in different countries with regard to delivery of care. To address these challenges the European Achondroplasia Forum (EAF), a network of senior clinicians and orthopaedic surgeons from Europe and the Middle East representative of the achondroplasia clinical community, came together with the overall aim of improving patient outcomes. The EAF developed a consensus on guiding principles of management of achondroplasia to provide a basis for developing optimal care in Europe. All members of the EAF were invited to submit suggestions for guiding principles of management, which were consolidated and then discussed during a meeting in December 2020. The group voted anonymously on the inclusion of each principle, with the requirement of a 75% majority at the first vote to pass the principle. A vote on the level of agreement was then held. A total of six guiding principles were developed, which cover management over the lifetime of a person with achondroplasia. The principles centre on the lifelong management of achondroplasia by an experienced multidisciplinary team to anticipate and manage complications, support independence, and improve quality of life. There is focus on timely referral to a physician experienced in the management of achondroplasia on suspicion of the condition, shared decision making, the goals of management, access to adaptive measures to enable those with achondroplasia to access their environment, and the importance of ongoing monitoring throughout adolescence and adulthood. All principles achieved the 75% majority required for acceptance at the first vote (range 91-100%) and a high level of agreement (range 8.5-9.6). The guiding principles of management for achondroplasia provide all healthcare professionals, patient advocacy groups and policy makers involved in the management of achondroplasia with overarching considerations when developing health systems to support the management of achondroplasia.

Stand-alone craniocervical decompression is feasible in children with mucopolysaccharidosis type I, IVA, and VI.

BACKGROUND CONTEXT: In patients with mucopolysaccharidosis (MPS), glycosaminoglycan deposits in the dura mater and supporting ligaments cause spinal cord compression and consecutive myelopathy, predominantly at the craniocervical junction. Disease characteristics of craniocervical stenosis (CCS) in patients with MPS differ profoundly from other hereditary and degenerative forms. Because of high periprocedural morbidity and mortality, patients with MPS pose a substantial challenge to the inexperienced medical care provider. As literature remains scarce, we present our experience with a large cohort of patients with MPS treated for CCS without atlanto-occipital instrumentation. PURPOSE: The present study aimed to describe a safe and least traumatic approach for treating CCS in children with MPS, avoiding primary instrumentation. STUDY DESIGN: This is a prospective follow-up (cohort) study. PATIENT SAMPLES: We report 15 consecutive patients with CCS related to MPS, who were treated with stand-alone cervical decompression. OUTCOME MEASURES: Myelopathy was assessed using magnetic resonance imaging (MRI), somatosensory evoked potentials, and clinical evaluation. Cervical instability was evaluated using plain x-ray and MRI. The disability status is quantified using either the Karnofsky or Lansky Performance Score. METHODS: We describe 15 consecutive patients treated with craniocervical decompression. Data were collected prospectively. The mean follow-up is 6 years (5 standard deviation). The technique and treatment principles are described. RESULTS: The overall clinical outcome in this patient cohort is good (mean Karnofsky Performance Score of 80). No patient developed signs of C0-C1-C2 instability or progressive myelopathy. Restenosis occurred in seven patients, requiring a total of eight reoperations. CONCLUSIONS: Surgery in patients with MPS is associated with high morbidity and mortality of up to 4.2%. Because of the unique nature of the disease, recurring stenosis is inevitable. To shorten the procedure time and simplify the anticipated reoperation, we provide data that craniocervical decompression is feasible without the necessity of primary osteosynthesis. In the absence of craniocervical instability, decompression surgery without occipitocervical stabilization yields good postoperative results and challenges the long-standing paradigm of prophylactic craniocervical fixation.

First experiences with the implementation of the European standard EN 62304 on medical device software for the quality assurance of a radiotherapy unit.

BACKGROUND: According to the latest amendment of the Medical Device Directive standalone software qualifies as a medical device when intended by the manufacturer to be used for medical purposes. In this context, the EN 62304 standard is applicable which defines the life-cycle requirements for the development and maintenance of medical device software. A pilot project was launched to acquire skills in implementing this standard in a hospital-based environment (in-house manufacture). METHODS: The EN 62304 standard outlines minimum requirements for each stage of the software life-cycle, defines the activities and tasks to be performed and scales documentation and testing according to its criticality. The required processes were established for the pre-existent decision-support software FlashDumpComparator (FDC) used during the quality assurance of treatment-relevant beam parameters. As the EN 62304 standard implicates compliance with the EN ISO 14971 standard on the application of risk management to medical devices, a risk analysis was carried out to identify potential hazards and reduce the associated risks to acceptable levels. RESULTS: The EN 62304 standard is difficult to implement without proper tools, thus open-source software was selected and integrated into a dedicated development platform. The control measures yielded by the risk analysis were independently implemented and verified, and a script-based test automation was retrofitted to reduce the associated test effort. After all documents facilitating the traceability of the specified requirements to the corresponding tests and of the control measures to the proof of execution were generated, the FDC was released as an accessory to the HIT facility. CONCLUSIONS: The implementation of the EN 62304 standard was time-consuming, and a learning curve had to be overcome during the first iterations of the associated processes, but many process descriptions and all software tools can be re-utilized in follow-up projects. It has been demonstrated that a standards-compliant development of small and medium-sized medical software can be carried out by a small team with limited resources in a clinical setting. This is of particular relevance as the upcoming revision of the Medical Device Directive is expected to harmonize and tighten the current legal requirements for all European in-house manufacturers.

Development of a Scoring System to Evaluate the Severity of Craniocervical Spinal Cord Compression in Patients with Mucopolysaccharidosis IVA (Morquio A Syndrome).

BACKGROUND: As spinal cord compression at the craniocervical junction (CCJ) is a life-threatening manifestation in patients with mucopolysaccharidosis (MPS) IVA, surgical decompression should be performed before damage becomes irreversible. We evaluated the diagnostic value of several examinations for determining the need for decompression surgery. METHODS: We retrospectively analysed results of clinical neurological examination, somatosensory evoked potential (SEP) and magnetic resonance imaging (MRI) in 28 MPS IVA patients. A scoring system - based on the severity of findings - was used to compare results of patients with and without indication for decompression surgery. Individual test scores and two composite scores were evaluated for their potential to assess severity of CCJ impairment. RESULTS: Sixteen patients had an indication for surgery; 12 of them had undergone surgery. Twelve patients had no indication for surgery; none had received surgery. Neurological (P = 0.004), MRI (P < 0.001) and atlantoaxial subluxation (P = 0.006) scores, but not SEP and odontoid hypoplasia scores, differed significantly between patients with and without surgical indication. Both the abbreviated CCJ score, i.e. sum of neurological and MRI scores, and the extended CCJ score, i.e. sum of abbreviated CCJ and atlantoaxial subluxation score, discriminated between patients with and without surgical indication (abbreviated: 0-2 points vs 2-5 points, P < 0.001; extended: 0-3 points vs 3-7 points; P < 0.001). Although CCJ instability plays a major role in cervical cord pathology, decompression surgery without occipito-cervical stabilisation may yield good postoperative results. CONCLUSIONS: The abbreviated and extended CCJ scores are objective, transparent and reproducible tools for assessing the CCJ pathology and the need for surgery.

Spinal involvement in mucopolysaccharidosis IVA (Morquio-Brailsford or Morquio A syndrome): presentation, diagnosis and management.

Mucopolysaccharidosis IVA (MPS IVA), also known as Morquio-Brailsford or Morquio A syndrome, is a lysosomal storage disorder caused by a deficiency of the enzyme N-acetyl-galactosamine-6-sulphate sulphatase (GALNS). MPS IVA is multisystemic but manifests primarily as a progressive skeletal dysplasia. Spinal involvement is a major cause of morbidity and mortality in MPS IVA. Early diagnosis and timely treatment of problems involving the spine are critical in preventing or arresting neurological deterioration and loss of function. This review details the spinal manifestations of MPS IVA and describes the tools used to diagnose and monitor spinal involvement. The relative utility of radiography, computed tomography (CT) and magnetic resonance imaging (MRI) for the evaluation of cervical spine instability, stenosis, and cord compression is discussed. Surgical interventions, anaesthetic considerations, and the use of neurophysiological monitoring during procedures performed under general anaesthesia are reviewed. Recommendations for regular radiological imaging and neurologic assessments are presented, and the need for a more standardized approach for evaluating and managing spinal involvement in MPS IVA is addressed.

Craniocervical decompression in patients with mucopolysaccharidosis VI: development of a scoring system to determine indication and outcome of surgery.

OBJECTIVE: To analyse diagnostic value of somato-sensory evoked potentials (SEP), magnetic resonance imaging (MRI), and clinical neurological examination in the decision for decompression surgery in mucopolysaccharidosis (MPS) VI patients with craniocervical cord compression (CCJ). METHODS: We retrospectively analysed neurological examination, SEP of the median nerve and MRI outcomes from 31 MPS VI patients. Individual scores for each test (based on severity of findings) and a sum of scores of all three procedures (CCJ score) were evaluated for their potential to measure the need for and improvement after surgery. Differences between rapidly and slowly progressive patients were also evaluated. RESULTS: Fourteen patients (45 %) aged 4-34 years underwent decompression surgery. Median age at first operation was lower in rapidly than in slowly progressive patients (12 vs. 24 years; P = 0.008). Neurological and SEP findings but not MRI results differed significantly between non-operated and operated patients (P < 0.001, P = 0.003 and P = 0.08, respectively). A significant relationship was found between MRI and clinical neurological examination (P < 0.001) and between SEP and clinical neurological examination (P = 0.01) but not between MRI and SEP (P = 0.06). The CCJ score discriminated between operated and non-operated patients (4-9 points vs. 0-3 points; P < 0.001) and decreased in 61.5 % of patients after surgery. CONCLUSIONS: CCJ is common in rapidly and slowly progressive MPS VI patients. The CCJ score is an objective and transparent tool for assessing pathology of the CCJ, the need for surgery, and improvement after surgery.

Dopaminergic modulation of long-lasting direct current-induced cortical excitability changes in the human motor cortex.

Dopaminergic mechanisms participate in N-methyl-D-aspartate (NMDA) receptor-dependent neuroplasticity, as animal experiments have shown. This may be similar in humans, where dopamine influences learning and memory. We tested the role of dopamine in human cortical neuroplasticity. Changes of excitability were induced by transcranial direct current stimulation (tDCS). D2 receptor blocking by sulpiride abolished the induction of after-effects nearly completely. D1 activation alone in the presence of D2 receptor blocking induced by co-administration of sulpiride and pergolide did not re-establish the excitability changes induced by tDCS. This suggests that D2 receptors play a major supporting role in inducing neuroplasticity in the human motor cortex. Enhancement of D2 and, to a lesser degree, D1 receptors by pergolide consolidated tDCS-generated excitability diminution until the morning after stimulation. The readiest explanation for this pattern of results is that D2 receptor activation has a consolidation-enhancing effect on tDCS-induced changes of excitability in the human cortex. The results of this study underscore the importance of the dopaminergic system for human neuroplasticity, suggest a first pharmacological add-on mechanism to prolong the excitability-diminishing effects of cathodal tDCS for up to 24 h after stimulation, and thus render the application of tDCS practicable in diseases displaying enhanced cortical excitability, e.g. migraine and epilepsy.

No correlation between moving phosphene and motor thresholds: a transcranial magnetic stimulation study.

The aim of this study was to investigate the temporal stability of moving phosphenes and to assess whether moving phosphene thresholds (PTs) correlate with motor thresholds (MTs). Small moving sensations, so-called moving phosphenes, are perceived when V5, an area important for visual motion analysis, is stimulated by transcranial magnetic stimulation (TMS). However, it is still a matter of debate if V5 phosphenes are stable sensations across measurements and if they are a reasonable index of the cortical excitability of V5. Currently, MT is more commonly used as an index of global cortical excitability. However, previous studies have indicated that stationary PTs are suitable alternatives when the primary visual cortex is stimulated by TMS. Using paired-pulse TMS, stationary and moving PTs and applying single pulse TMS, MTs were measured in 11 subjects. PTs were retested in nine subjects 5-7 days later. Stationary and moving PTs were stable within subjects across the two sessions and showed a high inter-correlation. Conversely, PTs and MTs did not correlate. Our results are in agreement with previous studies showing that excitatory measurements of one specific cortex cannot be generalized to the excitability of the whole cortex. Thus, we propose specific measures for cortices of interest: PT for visual experiments and MT for motor experiments.